PROJECT SUMMARY: The specific mechanisms that elicit breast cancer metastasis are still the subject of study. However, an implicit assumption is that they occur as a consequence of cells shed from breast tumors that have entered peripheral and/or lymphatic circulation;subsequent cell-cell interactions with the vascular endothelium lead to adhesion and extravasation from circulation. Our studies of mouse models of allergic pulmonary inflammation have demonstrated that the proposed pathways leading to metastasis have significant similarities with the mechanisms mediating allergen-induced tissue-specific recruitment of leukocytes. In particular, the activation of the lung vascular endothelium is an underlying mechanism required by circulating pro-inflammatory cells to mediate firm adhesion and eventual diapedesis into the pulmonary parenchyma. We have capitalized on these allergic asthma studies and have utilized a melanoma cell transfer model of metastasis to demonstrate that relative to allergen-naive control animals, the number of pulmonary metastases in allergic mice is significantly increased. In addition, these preliminary studies showed that the increase in metastasis was T cell dependent and was effectively blocked with drugs commonly used to treat asthma patients (e.g., inhaled corticosteroids). Thus, the data suggest that pulmonary allergic inflammation generates an environment favorable for adhesion and extravasation of circulating cancer cells. Moreover, the evolutionarily conserved character of these trafficking mechanisms suggests valid extrapolation of this mouse model data to human patients. The Central Hypothesis of this application is that allergen-induced activation of the pulmonary vascular endothelium associated with asthma increases the rate of metastasis to the lung. Collectively, our preliminary studies showed that allergic pulmonary inflammation results in a significant increase in the probability of metastasis to the lungs of mice as compared to non-allergic animals. More significantly, further studies also examined a breast cancer patient database and showed that a similar correlation likely exists in humans. The objectives of this application will be achieved through a nested case-control study within an underlying cohort of breast cancer patients whose disease progression has led to distant metastasis. The Specific Aim of this application is to determine if the odds of a prior diagnosis of asthma is greater among women with lung metastasis (cases) compared to women with metastasis to other distant sites (controls). Our long term goal is the eventual translation of this retrospective study into a larger more comprehensive prospective study defining specific parameters of this potential relationship. PUBLIC HEALTH RELEVANCE: RELEVANCE: The importance of establishing a link between breast cancer metastasis and asthma is difficult to overestimate given the remarkable rise in the incidence of asthma among women, which has led to nearly 1 in 10 adult women in the United States (including those with breast cancer) being diagnosed with this disease. We believe that the completion of this application has the potential of leading to therapeutic pulmonary regimes (e.g., enhanced treatment protocols) aggressively targeting the asthma of breast cancer patients with the expectation of increased survival rates among this large subset of breast cancer patients.